Fig. 7. Simplified schematic diagram of a conceptual “feed-forward-loop” model of DAMP-induced cytokine storm in respiratory viral infection.

Virus-induced RN (necroptosis and pyroptosis) leads to release of constitutive DAMPs such as HMGB1 and DNA that activate PRR-bearing alveolar macrophages, which in turn secrete cytokines such as TNF and type I IFNs. These cytokines operate as inducible DAMPs to induce necroptosis. Release of constitutive DAMPs such as HMGB1 and eATP induces pyroptosis, which again is associated with release of the constitutive DAMPs and IL-1β. The constitutive DAMPs such as HMGB1 and DNA activate recruited PRR-bearing neutrophils, which contribute to further cytokine production such as TNF and type I IFNs. The sequelae of processes are repeated in terms of a feed-forward-loop and might proceed to a vicious circle. AECI alveolar epithelial type I cells, cDAMPs constitutive DAMPs, eATP extracellular ATP, HMGB1 high mobility group box 1, iDAMPs inducible DAMPs, IFN interferon, IFNAR type I interferon receptor, IL interleukin, MØ macrophage, P2XR7 purinergic receptor P2X7, RN regulated necrosis, TLR Toll-like receptor, TNF tumor necrosis factor, TNFR1 tumor necrosis factor receptor 1, vc vicious circle. Note: the oversimplified figure shows only one example out of various possible scenarios regarding release of DAMPs, expression of pattern recognition receptors, secretion of cytokines (iDAMPs), type of cells involved, and sequelae of processes. Also note: injured alveolar epithelial type I cells are representative for other injured cells such as alveolar epithelial type II cells and endothelial cells. In particular, the target role of the endothelium is not shown. Sources: [45, 121, 123].